Type II collagen-induced arthritis (CIA) is an experimentally induced and genetically controlled autoimmune model of chronic, peripheral arthritis. Multiple genes are involved. An inbred rat colony of susceptible and resistant, congenic, prototype and recombinant rat strains is being used to elucidate several parameters of CIA that directly relate to joint inflammation in rheumatic disease patients. 1) The existence of a genetic relatedness between susceptibility to arthritis and to autoimmune diseases is being questioned by comparative strain analysis of susceptibility to CIA and other experimental models of arthritis. 2) To determine if differences in susceptibility to CIA are related to differences in specificity of the immune response to type II collagen, antisera from resistant and susceptible strains are being analyzed (by ELISA) for relative reactivity with isolated helical cyanogen-bromide (CB) peptides of rat collagen (II). 3) Strains of the RT1 haplotype are low responders and CIA-resistant. Intra-RT1 recombinants will be used to identify the RT1 subregion that controls anti-collagen immune reactivity. To test for collagen-specific T-suppressor cells, non-arthritogenic adjuvants will be used during immunization. 4) The existence of specific "arthritogenic" regions of the collagen molecule is proposed and will be tested in two approaches: a) immunization with individual CB peptides prepared biochemically from heterologous type II collagens; b) use of hybridoma technology to prepare a panel of monoclonal antibodies reactive with rat collagen (II) which will be tested for ability to passively transfer arthritis to unimmunized rats. 5) Tissue culture techniques are being used to investigate the interaction of synovial cells, collagen, and immune T-cells with emphasis on the roles of interferon and interleukins. Genetic differences between susceptible and resistant rats, in the production of or response to these immunomodulators will be questioned.